Combining gold(I/III) complexes and ferrociphenol scaffold for the generation of bimetallic complexes with anticancer activity

Abstract

A series of eleven heterobimetallic Au/Fe complexes featuring [Au(I)-thioglucose tetraacetate], [Au(I)-NHC], [(C^N)Au(III)Cl], [(C^N^C)Au(III)] or [(C^C)Au(III)Cl] fragments and (diphenylphosphino)ferrociphenol or (diphenylphosphino)ferrocene ligands have been synthesized. The compounds were fully characterized by NMR, high-resolution mass spectrometry, elemental analysis, as well as by X-ray diffraction for the representative Au-carbene complex. The electrochemical behavior of the complexes was studied by cyclic voltammetry. While the compounds resulting from (diphenylphosphino)ferrocene displayed a reversible, ferrocene-centered redox process, their analogs obtained from (diphenylphosphino)ferrociphenol showed additional irreversible multielectron redox transitions attributable to the redox-active ferrociphenol fragment. The antiproliferative activity of the complexes was evaluated in vitro on lung (A549) and triple-negative breast (MDA-MB-231) cancer cells and compared to non-cancerous breast cells (MCF-10A). Coordination of the gold fragments by (diphenylphosphino)ferrocene led to the buildup of antiproliferative activity with EC50 down to the submicromolar level. Comparatively, the antiproliferative activities of the analogous bimetallic complexes containing the (diphenylphosphino)ferrociphenol ligand were slightly lower. The ability of the complexes to inhibit thioredoxin reductase (TrxR), an established target of both gold complexes and ferrociphenol, was also investigated, including in oxidative conditions. Bimetallic complexes featuring exchangeable ligands, such as in Au(I)−chlorido, thiolato, and (C^N) cyclometallated Au(III) fragments, showed half-maximal effective concentrations (EC50) values in the nanomolar range, typical of related gold complexes. In contrast, bimetallic complexes bearing stable scaffolds such as Au(I)-NHC (NHC = N-heterocyclic carbene) and bis-cyclometallated (C^N^C) Au(III) required oxidation of the ferrociphenol moiety to induce significant thioredoxin reductase inhibition.